This proposal is a continuation of research designed to investigate the behavioral reward mechanisms that may underlie the compulsive use of stimulant, opioid, and cannabinoid drugs. A reinforcement model of drug abuse provides the conceptual basis for the work. Briefly, it is assumed that abused drugs, such as cocaine and heroin, are powerful pharmacological reinforcers. The reinforcing properties of the drugs derive from their pharmacological similarities and functional interactions with the brain's natural reward mechanisms. It is furthermore assumed that natural reinforcers and drugs of abuse act ultimately at the cellular level and exert their behavioral effects by reinforcing the activity of individual brain cells. These questions will be evaluated primarily by use of two recently- developed operant conditioning methods for the localization of chemical reinforcement effects in the brain. In the first method (drug self- administration), a behavioral response will be reinforced by direct injections of transmitters or drugs into reward-related brain regions. In the second method ("cellular operant conditioning"), the bursting activity of neurons in brain slices from the same regions will be operantly conditioned by local extracellular applications of reinforcing transmitters and drugs. Appropriate pharmacological antagonists will be used to identify the brain receptors that may be associated with reinforcing effects in the two tests. The experimental plan proposes concurrent use of both operant conditioning methods in an attempt to correlate the reinforcing effects of transmitters and drugs at the behavioral and cellular levels. Other experiments will employ pertussis toxin and calcium agonists and antagonists to further investigate the potential for correspondence in the mechanisms of behavioral and cellular reinforcement. The proposed research could establish an entirely new conceptual framework for understanding drug abuse by demonstrating that the same operant- conditioning reinforcement mechanism underlies addiction at three levels-- cells, animals, and man.